Sphingolipid imbalance and inflammatory effects induced by uremic toxins in heart and kidney cells are reversed by dihydroceramide desaturase 1 inhibition

Feby Savira, Ruth Magaye, Carmen V. Scullino, Bernard L. Flynn, Stuart M. Pitson, Dovile Anderson, Darren J. Creek, Yue Hua, Xin Xiong, Li Huang, Danny Liew, Christopher Reid, David Kaye, Andrew R. Kompa, Bing Hui Wang

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7 Citations (Scopus)

Abstract

Non-dialysable protein-bound uremic toxins (PBUTs) contribute to the development of cardiovascular disease (CVD) in chronic kidney disease (CKD) and vice versa. PBUTs have been shown to alter sphingolipid imbalance. Dihydroceramide desaturase 1 (Des1) is an important gatekeeper enzyme which controls the non-reversible conversion of sphingolipids, dihydroceramide, into ceramide. The present study assessed the effect of Des1 inhibition on PBUT-induced cardiac and renal effects in vitro, using a selective Des1 inhibitor (CIN038). Des1 inhibition attenuated hypertrophy in neonatal rat cardiac myocytes and collagen synthesis in neonatal rat cardiac fibroblasts and renal mesangial cells induced by the PBUTs, indoxyl sulfate and p-cresol sulfate. This is at least attributable to modulation of NF-κB signalling and reductions in β-MHC, Collagen I and TNF-α gene expression. Lipidomic analyses revealed Des1 inhibition restored C16-dihydroceramide levels reduced by indoxyl sulfate. In conclusion, PBUTs play a critical role in mediating sphingolipid imbalance and inflammatory responses in heart and kidney cells, and these effects were attenuated by Des1 inhibition. Therefore, sphingolipid modifying agents may have therapeutic potential for the treatment of CVD and CKD and warrant further investigation.

Original languageEnglish
Pages (from-to)133-142
Number of pages10
JournalToxicology Letters
Volume350
DOIs
Publication statusPublished - 10 Oct 2021

Keywords

  • Des1 inhibitor
  • Dihydroceramide desaturase 1
  • Sphingolipids
  • Uremic toxins

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